Coumermycin derivatives



United States Patent Office iififfiii wherein corm/rnnMs zgli l iznlvATlvns R hydrogen or methyl, Donald Edward Nettleton, Jr., Jordan, N.Y., assignor to R1 15 2'tetrahydropyranyl Bristol-Myers Company, New York, N.Y., a corporation of Delaware 5 No Drawing. Filed Oct. 3, 1966, Ser. No. 583,992 Claims. (Cl. 260210) R and R are alike or different but are hydrogen or 2- ABSTRACT OF THE DISCLOSURE 10 y py are prepared by mixing together substantially pure cou- The (11-, tr1-, and tetra-tetrahydropyranylethers of coumermycin A1 or A2 with excess dihydropyran in the pres memfycin 1 and A2 are extremely ,valaable intermedi' ence of an acid catalyst and an inert solvent to yield $168 11] the preparation of novel derlvatives of coumermixtures of mom) dif UL and tetra tetrahydropyrany1 y 15 ether derivatives of cournermycin A or A respectively.

DETAILED DESCRIPTION BACKGROUND OF THE INVENTION This invention relates to new and useful derivatives of the antibiotic substances coumermycin A and coumermy- (1) Field of the invention: The di-, triand tetrahydrocin A (US. Patent 3,201,386) and to processes for their pyranyl ethers of the present invention are heretofore unproduction. More particularly, it relates to the di-, tri. known compounds that are valuable as intermediates in and tetra-tetrahyd-ropyranyl ethers of coumermycin A and the preparation of novel coumermycin derivatives. A and to the process of preparing same by reaction of (2) Description of the prior art: The compounds of the purified parent compound with dihydropyran in the the present invention are novel derivatives of the known presence of an acid catalyst. antibiotic agents coumermycin A and A of US. Patent Coumermycin A (R is methyl) and cournermycin A 3,201,386. (R is H) SUMMARY OF THE INVENTION Compounds having the formula 3E3 (31-13 H; C CH; 0 o o o 0 0 H3 c o HN o T CH3 H300 NBC-CH (fi-NH 0011.1 0 R1 o o R10 0 o a: H; o R2 o (3:0 o=o N H HN i i E H 0 o o 0 o 0 n3o 0 HN- o CH3 H300 NH- H (3NH -0oHi o R1 0 0 R 0 0 on on; on 5:0 0:0 NH HN are efiective in inhibiting the growth of Gram-positive bacteria. Both are nontoxic and exhibit a therapeutic efaration of compounds of the formula (5) Activated carboxylic acids such as F CCO H, F CHCO H,

wherein A, B and C are alike or different but are nitro, fluoro, cyano or hydrogen.

CH3 om H30 0 O 0 0 O 0 CH3 H3O 0 HN o You; H300 NH-Cli fi-NH OOH: OH I O O HO 0 OH OH: OH h=o c=o i N11 HN\ wherein (6) Alkylsulfonic acids having the formula R 1s hydrogen or methyl, R 15 Z-tetrahydropyranyl R (CH2)XSO3H R and R are alike or different but are hydrogen or 2- tetrahydropyranyl v The process is usually performed by mixing together substantially pure coumermycin A or coumermycin A with excess dihydropyran in the presence of an acid catalyst and an inert solvent to yield mixtures of mono, di-, triand tetra-tetrahydropyranyl ether derivatives of coumermycin A or A; respectively.

More specifically, a coumermycin is mixed together with dihydropyran in various molar proportions, but preferably in .a ratio of one mole of coumermycin to more than moles of dihydropyran.

The addition of a suitable acid to the coumermycindihydropyran mixture as a catalyst is essential. The acid employed is usually selected from one of the following groups.

(21) Concentrated mineral acids such as sulfuric acid, phosphoric acid, phosphorous acid, and hydrochloric acid.

(2) Arylsulfonic acids having the following formula in which each of A, B and C are alike or different and are hydrogen, halogen, (lower) alkyl, (lower) alkoxy, nitro, aryl, or cyano.

=(3) Lewis acids such as SnCl A101 B=F ZnCl FCC13.

(4) Acid resins in their acidic form (-H+) such as the phenolic sulfonic acids, polystyrene sulfonic acids, polystyrene phosphorous acids, polystyrene phosphonic acids, acrylic carboxylic acids, polystyrene nuclear sulfonic acids, methacrylic carboxylic acid, and in particular macroreticular polystyrene sulfonic acid (Amberlyst 15, Rohm & Haas).

wherein R is selected from the group consisting of aryl, substituted aryl, (lower)alkyl, substituted (lower)alkyl; and where x is a whole integer of 0 to 6 inclusive.

The quantity of the acid employed as the catalyst is usually determined by the reaction conditions, the bulk of the catalyst and the amount at which the optimum yield of product is obtained.

The reaction may be conducted with or without the use of a co-solvent, the co-solvent usually being employed to increase the solubility of the reactants and reduce the viscosity of the mixture. The co-solvent used is inert and is usually selected from the group consisting of tetrahydrofuran, dioxane, diethyl ether, the dipropyl ethers, the dibutyl ethers, benzene, xylene and toluene.

The reaction is exothermic. Its temperature can be carefully controlled or it can be allowed to seek its own level without substantial differences in the end result. The process is usually conducted at a temperature of 0-l00 C., but preferably in the temperature range of 25 to 60 C. for a period of time dependent upon the temperature used and ultimately upon the completion of reaction and the yields obtained.

As mentioned previously, the process usually results in the formation of mixtures of mono, di-, triand tetra substituted tetrahydropyranyl ether derivatives of the coumermycins. The ratio of the components of the mixture however, is largely dependent upon the reaction conditions, and most particularly the method of work-up and purification of same.

When the reaction is conducted at elevated temperatures of 60-80" C. for 2 to 4 hours, or at lower temperatures for longer periods of time, under very anhydrous conditions, followed by purification in the absence of polar solvents, there is obtained a product consisting of to 99% pure 2',2',4,4-0,0,0,0-tetratetrahydropyranylcoumermycin. The other possible tetrahydropyranylcoumermycins are usually found in the following order of their relative concentration: 2',2',4-0,0,0,-tritetrahydropyranyl 2,2' 0,0 ditetrahydropyranyl 2' O-monotetrahydropyranyl coumermycin.

When the reaction is conducted at lower temperatures, or for shorter periods of time, or under conditions not as anhydrous, the proportion of the 2,2',4,4-0,0,0,0- tetratetrahydropyranylcoumermycin in the mixture decrceases as the proportion of the other tetrahydropyranyl ethers increases.

It is a fact that the tetrahydropyranyl moiety attached to either or both 4-O-positions of the coumermycin molecule is quite labile in the presence of polar solvents. When 2,2',4,4-0,0,0,0-tetratetrahydropyranylcoumermycin or 2,2,4-0,0,0-tritetrahydropyranylcoumermycin is crystallized or recrystallized from a hot alcohol solvent system, the 4-0-tetrahydropyranyl ether functions are cleaved to 4- hydroxyl functions to yield pure 2',2-0,0-ditetrahydropyranylcoumermycin. The 2'-O-tetrahydropyranyl ether functions are generally stable when crystallization is carried out in the absence of acidic materials.

Resolution of mixtures of the tetrahydropyranyl ether derivatives can be accomplished by counter-current distribution purification. As a practical matter, the material is suitable as a mixture of di-, triand tetra-tetrahydropyranylcoumermycin, or it can be crystallized from a hot alcoholic solvent system to yield pure 2',2-0,0-ditetrahydropyranylcoumermycin, for use as an intermediate in its ultimate conversion to a biologically active agent.

2,2'-0,0 ditetrahydropyranylcoumermycin, 2,2,4- 0,0,0 tritetrahydropyranylcoumermycin, and 2',2,4,4 0,0,0,0-tetratetrahydropyranylcoumermycin, as pure entities or mixtures thereof, are valuable as intermediates in the preparation of extremely pure coumermycin A or A The mixing of either of the above compounds or mixtures thereof in an alcoholic solvent in the presence of a catalytic amount of acid (selected from those described above) results in the cleavage of all tetrahydropyranyl linkages in the molecule. Subsequent isolation of the product yields purified coumermycin A or A depending upon the starting material.

-2',2 0,0 ditetrahydropyranylcoumermycin, 2',2',4- 0,0,0 tritetrahydropyranylcoumermycin or 2',2',4,4 0,0,0,0 tetratetrahydropyranylcoumermycin, as pure entities or mixtures thereof, are also valuable as intermediates in the production of new and biologically active compounds. The treatment of one of the above, or a mixture of two or all three with an acylating agent will cleave the coumermycin molecule at either one or both a-amide linkages between the coumarin and pyrroledicarboxylic acid moieties to form compounds of the formulas CH3 :3 o O\ O o moon NHCR4 o 0 on =o NH if plus E EN 0 O\ O 0 A32: no ]3NH1/@/ Doom CH3 0 or t O O o EN I and/or wherein R is either hydrogen or methyl, and R is (lower)alkyl or aryl.

More specifically, an acylative cleavage of the di-, trior tetra-tetrahydropyranyl ethers of coumermycin A or mixtures thereof, is performed by mixing the above with quantities of benzoyl chloride, benzoyl bromide or benzoic acid anhydride in pyridine. Heating the mixture at temperatures below the boiling point for several hours or keeping it at room temperature for several days results in the production of material having the formula r 0 O O O OCH:

I O=C O O u @o-rvn 0cm which exhibits antibiotic activity in mammals against Staphylococcus aureus.

The standard coumermycin A assay is run on Petri plates prepared by using ten ml. of Baltimore Biological Laboratories (BBL) base agar and a top layer of four ml. of BBL seed agar inoculated with Staph. aureus ATCC 65381. The plates are incubated for 18 hours at 30 C. A standard activity curve for coumermycin A is determined by using concentrations in the range of 0.07 to 1.5 g/ml.

In the instant invention, use of the word coumermycin without specifically stating coumermycin A or A shall be taken to mean either coumermycin A or A or their derivatives, said compounds being chemically equivalent in this process.

The objectives of the present invention have been achieved, by the provision according to the present inven- 7 8 tion, of the process for the production of compounds mum temperature (below 40 C.) and the residue remainhaving the formula ing dissolved in boiling acetone (30 ml.). Hot ethanol CH3 CH3 H30 0 0 0 I o 0 CH3 Hao o HN- 0 on3 H500 NEE-("7 fiF-NH 0cm 0 0 0 0 C) /O 0R3 CH3 OR: 0 C) 0:0 0:0 I NH HN l wherein was slowly added with stirring and heating until 100 ml.

R and R are alike or different but are either hydrogen 2O gzg g ifi 3: 32 38 gg gi i j) g gig if i ggg ggfi or additional 810 mg. (13%) separated as a second crop 0 from the mother liquor after standing at C. for 24 hours.

A sample (1.7 g.) was recrystallized twice from acetone-ethanol to give a pure sample (1.5 g.), M.P. de-

and composition 200 C. Analysis.Calcd. for C65H75022N5: C, H, R18 elther hydrogen or methyl; N, 5.47. Found: c, 61.00; H, 5.83; N, 5.56. Neutral which comprises mixing together a compound having the equivalent! found, 623863161 formula CH3 CH3 H30 0 o 0 0 o 0 CH3 H 0 o HNH o CH H300 NH |3 I (J-NH 00H: 0.. y HO O H CH3 I x=o o=o I he em I R R with excess dihydropyran, but preferably in a ratio of EXAMPLE 2 one mole of coumermycin A or A to more than 20 moles of dihydropyran, and a strong acid catalyst se- 2,2'-0,0-ditetrahydropyranylcoumermycin A;

lected from the group consisting of mineral acids, arylsulfonic acids, Lewis acids, acid resins, activated carboxylic acids and alkylsulfonic acids, but preferably with arylsulfonic acids or strong acid resins, with or without 5 the presence of an inert solvent, but preferably with the Catalyst, Amberlyst 15 165111 (cohtalhlhg less than presence of a solvent selected from the group consisting 2 AS Stirring Was Continued additional 25 of tetrahydrofuran, dioxane, diethyl ether, the dipropyl Of DHP was addedsome coumermyclh Separated as ethers, the dibutyl ethers, benzene, xylene and toulene, at c a temperature in the range of 0l00 C., but preferably The exothermic reaction was maintamed at 30-35 C.

at a temperature in the range of 1050 C., and most by the use of an icewatef hath Q after 1 t0 hours preferably at about room temperature, for a perio f the gel gradually returned to solution. When solution was time usually determined by the temperature at which the attaihed, the exothermic reaction subsided; h' Was Process is conductcd, the lower the temperature the contmned another 2 to 3 hours (total reaction time about longer the time but usuahy f a period f time of 15 0 4 hours) during which time the solution darkened to an minutes to 200 hours. oran 11 In the preferred embodiments of the present invention, The Amherlyst Teslh Was removed y filtl'atlon n th Coumermycin A (5.5 g.) was stirred with 50 ml. THF (tetrahydrofuran) at room temperature until dissolution was complete. DHP (25 ml.) was added followed by the R iS as d fi d above and iS especially methyl, 2 and solution concentrated in vacuo to a syrup. Dilution of the 3 are hydrogen syrup with methanol (500 ml.) resulted in the formation EXAMPLE 1 5 of a crystalline solid which was washed with a little methanol, then dried, to yield 6.06 g. (93%) of roduct. 2 7OO'dltetrahydropyranylcoumermycm A1 The crude product was dissolved in a mixtfire of meth- Finely ground coumermycin A 5.5 g. (the free acid, M101 and methylene Chloride s purified by recrystallization as the sodium salt), was l t n i g S m W t diffi ult. The solution was slurried in 50 ml. DHP (dihydropyran) and a trace of 7 warmed to a boil and methanol added to the cloud point toluenesulfonic acid (2-3 mg.) was added. The mixture (about 30 required) AS the mix cooled, methylene was stirred magnetically in a stoppered flask under chloride was added in quantities just sufi'icient to mainhydrous conditions at 25 C. for 3%. hours, dissolution n a Clear Solution at mom temperature of the solid being complete in this case after 2 hours. p Standing he product Slowly crystallized in fine The solution was evaported to dryness in vacuo at minineedles. Yield: 3.96 g. (62%). Another 1.26 g. (20%) was obtained from the mother liquor by dilution with methanol.

The reaction temperature may be permitted to rise without cooling, with no ill elfect; in fact in larger scale reactions the heat of reaction may be advantageous. On large scale runs the reaction mixture was stirred for 24 hours, during which time the reaction mixture returned to ambient temperature (usually in the first 6 hours). In most cases, the material after the first methanol precipitation was used for further work. If this material has more than 2 g./mg. activity by coumermycin A assay, or if significant amounts of coumermycin (Rf -0.3) and/ or its monotetrahydropyranyl derivatives (Rf=0.45 0.50) are found present, it is recycled through the process. The Rf values are obtained using thin layer chromatography plates prepared from silica gel in a solvent system consisting of 9:21:8 (parts by volume) of methyl acetate 2-propanol concentrated NH OI-I.

EXAMPLE 3 Di-, tri-, and tetra-tetrahydropyranylcoumermyciu A mixture and its resolution Coumermycin A was stirred with THF at room temperature until dissolution occurred. DHP was added followed by Amberlyst 15 (H resin (containing less than 0.5% H As stirring continued, additional DHP was added. A gel formed that re-dissolved after one to two hours. Stirring was continued overnight at room temperature during which time the solution was darkened to an orange-brown color.

The Amberlyst resin was removed by filtration and the solution concentrated in vacuo to a syrup. Dilution of the syrup with a minimal quantity of methanol yielded a crude solid (85-95% of theory). The solid was dried in vacuo. Thin layer chromatography indicated flie solid consisted of at least three zones (R 0.6-0.7).

A Craig counter-current distribution separation was run on a 15 g. sample of the mixture using /2 volume upper phase to 1 volume lower phase from a system of :1:5 .1 of CCl :CHCl :CH OI-I:H O over 1001 transfers, 97.5% of the solid being recovered in total. The recoveries from the major concentrations as determined by ultra violet absorption at 345 m were as follows:

2',2',4,4-0,0,0,0-tetratetrahydropyranyl-coumermycin A The tetra-substituted tetrahydropyranyl ether of coumermycin A was recovered from tubes 21 through 40 as a pure crystalline solid, 3.68 g., M.P. decomposition above 200 C.

Analysis.Calcd. for C75'I'I91N5O24I C, 62.27; H, 6.34; N, 4.84. Found: C, 62.03; H, 6.31; N, 4.94.

2',2',4-0,0,0-tritetrahydropyranylcoumermycin A The tri-substituted tetrahydropyranyl ether of coumermycin A was recovered from tubes 41-70 as a pure crystalline solid, 3.8 g., M.P. decomposition above 200 C.

AnaZysis.-Calcd. for Cq0Hg3N5O23: C, 61.71; H, 6.14; N, 5.14. Found: C, 61.65; H, 6.19; N, 5.34.

2,2-0,0-ditetrahydropyranylcoumermycin A The di-substituted tetrahydropyranyl ether of coumermycin A; was recovered from tubes 71-100 as a pure crystalline solid, 1.8 g., M.P. decomposition above 200 C. The product was identical in its physical characteristics to previously characterized material.

2-O-monotetrahydropyranylcoumermycin A The mono-substituted tetrahydropyranyl ether of coumermycin A was recovered from tubes 101-430 as a pure crystalline solid, 1.6 g., M.P. decomposition above 200 C.

Analysis.Ca1cd. for C H N O C, 60.35; H, 5.66; N, 5.86. Found: C, 60.42; H, 5.81; N, 5.83.

Coumermycin A was recovered unreacted from tubes 300-499, 1.5 g., M.P. decomposition 240245 C., said product being identical in its physical characteristics to previously characterized material.

10 EXAMPLE 4 2',2'-0,0-ditetrahydropyranylcoumermyciu A Coumermycin A is stirred with THF at room temperature until solution is attained. DHP and several drops of concentrated H HCl, or H PO are added and the stirring is continued for approximately four hours. Five grams of finely powdered N32CO3 are added to destroy the acid. Decantation followed by removal of the solvent in vacuo gives a syrup, which upon dilution with methanol crystallizes to a solid. Recrystallization of the solid from methanol, a methanol-halogenated hydrocarbon mixture or methanol-acetone mixture yields pure product, M.P. decomposition above 200 C., identical with previously characterized material.

EXAMPLE 5 2,2'-0,0-ditetrahydropyranylcoumermycin A Coumermycin A (1110.06 g., 1.0 mole) was slurried in a mixture of 11.2 liters of dry THF and 11.2 liters of dry DHP. p-Toluenesulfonic acid monohydrate (22.2 g.) was added and the solution was stirred for twenty hours at room temperature. The solution was concentrated to /3 of the volume in vacuo at less than 40 C., filtered and the filtrate poured into 134 liters of dry methanol at 0 C. The product crystallized upon stirring for 30 minutes at 0-5 C. and was collected by filtration. The filter cake was covered by dry solvent at all times while washing same with 10 liters of dry, cold methanol, followed by 5 liters of petroleum ether.

Recrystallization from hot methanol yielded the desired 2,2-0,0-ditetrahydropyranyl ether.

EXAMPLE 6 2',2-0,0-ditetrahydropyranylcoumermycin A Substitution in the procedure of Examples 1, 2, 3, 4, or 5 for the coumermycin A used therein of coumermycin A produces 2',2'-0,0-ditetrahydropyranylcoumermycin EMMPLE 7 2',2',4,4-0,0,0,0-tetratetrahydropyranylcoumermycin A Substitution in the procedure of Example 3 for the coumermycin A used therein of coumermycin A produces 2',2,4,4 0,0,0,0 tetratetrahydropyranylcoumermycin A EXAMPLE 8 2,2',4-0,0,0-tritetrahydropyranylcoumermycin A Substitution in the procedure of Example 3 for the coumermycin A, used therein of coumermycin A produces 2',2',4-0,0,0-tritetrahydropyranylcoumermycin A EXAMPLE 9 2-O-monotetrahydropyranylcoumermycin A Substitution in the procedure of Example 3 for the coumermycin A used therein of coumermycin A produces 2'-O-monotetrahydropyranylcoumermycin A EXAMPLE 10 Coumermycin A via its tetrahydropyranyl ethers 2',2-0,0-ditetrahydropyranylcoumermycin A 2',2,4- 0,0,0-tritetrahydropyranylcoumermycin A 2',2,4,4-0, 0,0,0-tetratetrahydropyranylcoumermycin A or mixtures thereof are readily cleaved to a purified coumermycin A by dissolving the ethers in an alcohol or alcoholacetone solvent along with a catalytic amount of p-toluenesulfonic acid, followed by stirring for several hours. The purified coumermycin A obtained by the procedure is usually of superior quality and compares favorably to that prepared by other purification methods.

I 1 EXAMPLE 11 2',2-0,0-ditetrahydropyranylcoumermycin A via 2',2',4, 4-0,0,0,0-tetratetrahydropyranylcoumermycin A 2', '-0,0-ditetrahydropyranylcoumermycin A via 2',2',4-

0,0,0-tritetrahydropyranylcoumermycin A Pure 2',2',4-0,0,0 tritetrahydropyranylcoumermycin A obtained from Example 3, is dissolved in hot methanol, the solution concentrated in vacuo and the solid allowed to crystallize on cooling to yield pure 2,2'-0,0- ditetrahydropyranylcournermycin A M.P. decomposition above 200 C., identical with material previously characterized.

EXAMPLE 13 N-benzoyl-3-amino-4-hydroxy-8-methyl-7- 3 -O- (5 methyl-Z-pyrrolyc arbonyl) noviosyloxy] coumarin Sixteen grams of a mixture of di-, triand tetra-tetrahydropyranylcoumermycin A was dissolved in 35 ml. of

freshly distilled pyridine. Benzoyl chloride (6.6 ml.) was added directly and carefully to the stirred solution at 25 C. over a ten minute period and then stirred at room temperature a total of 124 hours. The deep orange solution was concentrated in vacuo to approXimatelyjO ml. and poured into 2000 ml. of vigorously stirred ice water. The pH was adjusted to 5.0 with 6 N hydrochloric acid (500 1111.), then stirred at 05 C. for one hour. The pink H30 0 g H 00 CH; off 0 R3 on. o 2

12 amorphous solids were vacuum filtered, washed with water and vacuum dried to yield 19.6 g. of solid, Staphylococcus aureus plate assay equivalent to 0.51 ,ug/mg. (compared to standard coumermycin A Treatment of the solid using the tetrahydropyranyl ether cleavage reaction described in Example 9 yielded 19 g. of a red crystalline residue, Staphylococcus aureus plate assay equivalent to 8.5 ,ug/mg. Fractional crystallization from ethyl acetate-Skellysolve B (petroleum hydrocarbon, B.P. -68 C., essentially n-hexane) yielded 5.6 g. of light yellow crystalline product, M.P.: tans and softens C., decomposes vigorously at 230-235 C., Staph. aureus plate assay equivalent to 54 ,ug/mg.

Analysis.-Calcd. for C H O N C, 62.83; H, 5.45; N, 4.73. Found: C, 63.49; H, 5.78; N, 4.43.

Initial studies performed on laboratory animals indicate that oral or intramuscular administration results in blood levels determined to be of therapeutic eflicacy.

While in the foregoing specification various embodiments of this invention have been set forth in specific detail and elaborated for the purpose of illustration, it will be apparent to those skilled in the art that this invention is susceptible to other embodiments and that many of the details can be varied widely without departing from the basic concept and the spirit and scope of the invention.

I claim:

1. A compound of the formula OCH3 wherein R and R are the same or difierent but are each hydrogen or and R is either hydrogen or methyl. 2. A compound of claim 1 having the formula HNW O NH-C i CNH tyt O O O OOH;

wherein R is either hydrogen or methyl.

3. A compound of claim 1 having the formula CH; CH:

1130 o o o o 0 0 H30 0 HN-T 0 CH3 HaCO NH 3 C-NH CH: O O O H H3 0 C=O I NH HN I wherein R is either hydrogen or methyl.

4. A compound of claim 1 having the formula wherein R is either hydrogen or methyl.

5. A compound of claim 1 having the formula C 3 H30 0 0 O O o 0 CH: H40 0 HNT O CH: HaC NH-C C-NH OCH: ('5 3 O O O 0 0 wherein R is either hydrogen or methyl.

6. The process for the production of compounds of the 15 16 wherein with excess dihydropyran and a catalytic amount of an R and R are alike or different but are hydrogen or acid selected from the group consisting of mineral acids, 0 arylsulfonic acids, Lewis acids, strong acid resins, activated carboxylic acids and alkylsulfonic acids, in an inert 5 solvent.

8. The process of claim 6 for the production of compounds of the formula R is either hydrogen or methyl;

which comprises mixing together a compound having the formula wherein R is either hydrogen or methyl; with excess dihydropyran and a catalytic amount of a strong acid.

7. The process of claim 6 for the production of compounds of the formula H30 0 o O CH: H3O CH;

H300 CH:

o I I 0=o o= NH HN I which comprises mixing together a compound having the formula CH3 CH3 H30 0 0 0 0 0 0 CH: H30 To HN[ 0 cm H300 NHQV HJNH com 011 0 0 H0 OH OH; H 0:0 0: I NH EN (13H: CH:

which comprises mixing together a compound having the formula CH1 OH; H30 CH;

0 0 0 0 0 0 H3O -O HN-L O CH; H300 JNH-C C-NH on,

OH (1) H0 H OH; H 0:0

with excess dihydropyran and a catalytic amount of an with excess dihydropyran and a catalytic amount of an acid selected from the group consisting of mineral acids,

arylsulfonic acids, Lewis acids, strong acid resins, actiacid selected from the group consisting of mineral acids, 20 vated carboxylic acids and alkyisulfonic acids, in an inert arylsulfonic acids, Lewis acids, strong acid resins, activated carboxylic acids and alkylsulfonic acids, in an inert solvent.

9. The process of claim 6 for the production of compounds of the formula solvent.

10. The process of claim 6 for the production of compounds of the formula 0 31: U 0 P U which comprises mixing together a compound having the formula 19 20 which comprises mixin together a compound having the with excess dihydropyran and a catalytic amount of an formula acid selected from the group consisting of mineral acids,

arylsulfonic acids, Lewis acids, strong acid resins, activated carboxylic acids and alkylsulfonic acids, in an inert 5 solvent.

CH4 CH3 H30 0 0 0 o o 0 H3O ]o= HN-l' 0 CH; H300 NH-C- C-NH OCH:

OH 1; 1; H0 0 OH CH3 OH 3:0 0:0 N5 l (311: H:

References Cited Parham et aL: Jour. American Chem. S0c., vol. 70, 1948, pp. 4187-4189.

LEWIS GOTTS, Primary Examiner.

I. R. BROWN, Assistant Examiner.

UNITED STATES PATENT OFFICE Certificate of Correction Patent; No. 3,380,994 April 30, 1968 Donald Edward Nettleton, Jr.

It is certified that error appears in the above identified p Patent are hereby corrected as shown below Columns 1 and 2, second formula should appear as shown below on, cm me 0 o y o o 0 CH1 H10 0 HN\- 0 R10 R NH C--NH H0 ll 1!. A (J H G K: al H o nn nu atent and that said Letters 3 and 4, lines 12 to 26, the formula should appear as shown below columns NH 1i column 8,1ine 26, after composition insert-abpve-; column 9, line 40, 5: 1: 5.1 should read5: 1: 5: 1-; columns 11 and 12,1mes 29 to 48, the formula should appear as shown below:

- CHI o o o o o 0 me 0 1m-- 0 Y on, 11.0 o NH-i i-NE o on.

0 n: H, B o

lines 61 to 75, the formula should appear as shown below all? columns 13 and 14, the third formula should appear as shown below OCH:

HIC

mm c w Ham w a m .1 O0 1 c0 0 g l A 0 IC 0 IC 0 N\ m u m a 0 H O O H 0 .0 o 0 0 o m 0 0 c o c 0 w r r H o m. o W o O p 0 P o H a o n a o n m 4 0 d N 0 0 w cflo m nrflo m w n m n JVHO m H 000 m H CH0 H r .M v d on d on 0 IO O \O 0 I m 1 cl m v mm o v mm o 0 0 0 H I 0 0 f 0 o in 0 O i O 1 0 a 8 w M m a .I. w 3 w m H d mm m H w m n m S s n w m Signed and sealed this 14th day of October 1969.

[SEAL] Attest.

WILLIAM E. SCHUYLER, JR.,

Commissioner 0 f Patents. 

